Research location: University of Toronto - St. George Campus (downtown)

Primary Research Area: Cancer

Secondary Research Area: Molecular & Cell Biology

Research Statement:

Molecular mechanisms of cancer: understanding the role of tumour suppressors and oncoproteins in cancer biology

Horizontal Tabs Group

Research

Role of tumour suppressors and oncoproteins in cancer biology

Cancer is a genetic disease caused by alterations in tumour suppressor genes and oncogenes. Our research mission is to elucidate the molecular mechanisms governing the function of two major cancer-associated proteins called von Hippel-Lindau (VHL) tumour suppressor protein and RAS oncoprotein with the supposition that lessons learned would provide fundamental understanding of cell biology and lay the basic foundation for the development of rational anti-cancer therapeutics.

a. VHL in solid tumours

Oxygen is essential for eukaryotic life and inextricably linked to the evolution of multicellular organisms. Proper cellular response to changes in oxygen tension during normal development or pathological processes, such as heart disease and cancer, is ultimately regulated by the transcription factor called hypoxia-inducible factor (HIF). Tumour cells are inevitably challenged with limited oxygen availability as the growth of the tumour mass surpasses the diffusional capacity of oxygen from the nearest blood vessel. To overcome this crisis, tumour cells initiate the hypoxic response to trigger various adaptive responses, including anaerobic metabolism, angiogenesis and increased production of oxygen-carrying red blood cells. This is accomplished by the stabilization of HIF transcription factor, which escapes oxygen-dependent destructive targeting by VHL tumour suppressor-containing E3 ubiquitin ligase complex under hypoxia. Clinically relevant is the observation that mutation or loss of VHL causes VHL disease, which is characterized by the development of tumours in multiple organs such as the brain, spinal cord, retina, inner ear, pancreas, adrenal gland, and kidney. Furthermore, the extent of HIF expression correlates with disease aggressiveness and patient prognosis across a wide range of tumours from breast, prostate, and colon to kidney cancer; underscoring the importance of oxygen-sensing VHL-HIF pathway in oncogenesis.

b. RAS in human cancer

Mutations in RAS and various other components of the RAS signaling pathways are among the most common genetic alterations in human cancers and have also been identified in several developmental syndromes such as Noonan syndrome, Costello syndrome and cardiofaciocutaneous syndrome. The three human RAS oncogenes (H‐RAS, N‐RAS, and K‐RAS) encode highly related 188-189 amino acid proteins. They are canonical members of a large superfamily consisting of more than 150 cellular members of small monomeric GTPase proteins, which function as ‘molecular switches’ in a number of signaling pathways that regulate vital cellular functions. Like other GTP-binding proteins, RAS cycles between the inactive GDP and the active GTP bound forms through conformational changes near the nucleotide-binding site localized to the switch I and switch II regions. Over the past few decades, it has become clear that the activity or the oncogenic potential of RAS is dependent on the non-receptor tyrosine kinase Src to regulate essential cellular pathways for proliferation, differentiation and survival of eukaryotic cells. However, the precise molecular interplay between RAS and Src remains an outstanding mystery. Understanding the molecular mechanisms governing RAS will provide invaluable insights into the fundamental processes in cell biology and the pathogenesis of many forms of human cancer as well as numerous developmental syndromes.

Research Training and Opportunities

Our research approach is multidisciplinary with focus on molecular biology and protein biochemistry. The research environment is highly interactive with state-of-the-art equipment and facilities and is an excellent training ground for outstanding graduate students and postdoctoral fellows who wish to pursue a career in academia. Past members have garnered competitive national scholarships and been recruited to prestigious institutions such as MD Anderson Cancer Center, Memorial Sloan Kettering Cancer Center, Dana-Farber Cancer Institute, Stanford, Yale, M.I.T., and Harvard.

Training opportunities are currently available for prospective graduate students pursuing PhD or MD/PhD and for postdoctoral fellows. Candidates are encouraged to directly contact Professor Ohh.

Professor

Professor Ohh received his PhD from the University of British Columbia and was a Medical Research Council and National Cancer Institute of Canada postdoctoral fellow in the laboratory of Dr. William G. Kaelin Jr., Howard Hughes Investigator and National Academy of Science Member, at the Dana-Farber Cancer Institute and Harvard Medical School. Professor Ohh is known for his pioneering and paradigm-shifting work in the field of hypoxia signalling in normal and cancer cell biology, and has published seminal research articles in journals with broad readership, such as Nature Medicine, Cancer Cell and Science, with approximately 7,000 combined citations. Professor Ohh is a recipient of the Canadian Cancer Society Young Investigator Award, Premier’s Research Excellence Award, and Canada Research Chair in Molecular Oncology.